Alzheimer's disease is a disease that causes mature neurons to die via synaptic impairment. According to recent studies, Alzheimer's disease has found to develop stepwise. As the first stage, there is a stage in which synaptic impairment occurs chiefly, which is a reversible stage. As a stage subsequent to the reversible stage, there is a stage in which neuronal death occurs, which is an irreversible stage. It is considered that reaching this irreversible stage triggers the onset of Alzheimer's disease (Non-Patent Document 1).
The synaptic impairment is considered to occur mainly by the action of accumulated β amyloid (Aβ) dimers and dodecamers on glutamate receptors, and the like. However, neither Aβ dimers nor Aβ dodecamers induce neuronal death in vitro or in vivo (Non-Patent Document 2). Therefore, in order to analyze pathology of human Alzheimer's disease, it is necessary to clarify the cause and molecular mechanism of the neuronal death, which occurs in the irreversible stage subsequent to the reversible synaptic impairment stage.
Amylospheroids (ASPD) are unique Aβ assemblies that are toxic to neither non-neuronal cells nor immature neurons, but selectively cause functionally mature neurons to die (Non-Patent Document 1). First, amylospheroids were isolated as spherical Aβ assemblies about 10 nm in diameter, which cause neuronal death in vitro (Non-Patent Document 3). Later, antibodies specific to these synthetic amylospheroids were prepared (Patent Documents 1 and 2). Using these antibodies, amylospheroids formed in living bodies in brains of human patients with Alzheimer's disease (i.e., native amylospheroids) were isolated (Non-Patent Document 3). Based on studies using the native amylospheroids, the following have been clarified (Non-Patent Document 3): i) similarly to synthetic amylospheroids, native amylospheroids selectively induce cell death with respect to mature neurons; in correlation with the severity of Alzheimer's disease, the amount of native amylospheroids increases in cerebral cortex of patients with Alzheimer's disease with neuronal loss; and in cerebellum of patients with Alzheimer's disease with few neuronal loss, the amount of native amylospheroids is very small. Therefore, it is considered that amylospheroids play a central role in the irreversible stage that triggers the onset of Alzheimer's disease. Moreover, native amylospheroids are detected also in brains of patients with dementia with Lewy bodies (Non-Patent Document 1). Hence, it is considered that amylospheroids play a central role also in the onset of dementia with Lewy bodies.
Incidentally, although the amylospheroids and the Aβ dimers and Aβ dodecamers, which are considered as the main cause of synaptic impairment, are both Aβ assemblies, it is indicated that they are formed from Aβ monomers via different paths. Specifically, Aβ dimers and Aβ dodecamers are formed via Aβ dimers, whereas amylospheroids are formed from Aβ trimers (Non-Patent Document 4).